Microglia regulate central nervous system myelin growth and integrity

McNamara, Niamh; Munro, David A. D.; Bestard-Cuche, Nadine; Uyeda, Akiko; Bogie, Jeroen F. J.; Hoffmann, Alana; Holloway, R.; Molina-González, Irene; Askew, Katharine E.; Mitchell, Stephen; Mungall, William; Dodds, Michael; Dittmayer, Carsten; Moss, Jonathan; Rose, Jamie; Szymkowiak, Stefan; Amann, Lukas; McColl, Barry W.; Prinz, Marco; Spires‐Jones, Tara L.; Stenzel, Werner; Horsburgh, Karen; Hendriks, Jerome J. A.; Pridans, Clare; Muramatsu, Rieko; Williams, Anna; Priller, Josef; Miron, Véronique E.

doi:10.1038/s41586-022-05534-y

Cited by 191 publications

(141 citation statements)

References 52 publications

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…The central nervous system currently consists of three major cell types: neurons, astrocytes, and microglia [ 41 , 42 ]. Currently, microglia are reported to be mainly involved in immune function; the excessive release of pro-inflammatory factors and gasdermin activation in microglia will lead to the pyroptosis of the whole nervous system [ 43 , 44 ]. In the present study, evidence showed that only GSDME is expressed in hippocampal neuronal cells, not GSDMD.…”

Section: Discussionmentioning

confidence: 99%

A Pore Forming Toxin-like Protein Derived from Chinese Red Belly Toad Bombina maxima Triggers the Pyroptosis of Hippomal Neural Cells and Impairs the Cognitive Ability of Mice

Wang

Lee

et al. 2023

Toxins

View full text Add to dashboard Cite

Toxin-like proteins and peptides of skin secretions from amphibians play important physiological and pathological roles in amphibians. βγ-CAT is a Chinese red-belly toad-derived pore-forming toxin-like protein complex that consists of aerolysin domain, crystalline domain, and trefoil factor domain and induces various toxic effects via its membrane perforation process, including membrane binding, oligomerization, and endocytosis. Here, we observed the death of mouse hippocampal neuronal cells induced by βγ-CAT at a concentration of 5 nM. Subsequent studies showed that the death of hippocampal neuronal cells was accompanied by the activation of Gasdermin E and caspase-1, suggesting that βγ-CAT induces the pyroptosis of hippocampal neuronal cells. Further molecular mechanism studies revealed that the pyroptosis induced by βγ-CAT is dependent on the oligomerization and endocytosis of βγ-CAT. It is well known that the damage of hippocampal neuronal cells leads to the cognitive attenuation of animals. The impaired cognitive ability of mice was observed after intraperitoneal injection with 10 μg/kg βγ-CAT in a water maze assay. Taken together, these findings reveal a previously unknown toxicological function of a vertebrate-derived pore-forming toxin-like protein in the nerve system, which triggers the pyroptosis of hippocampal neuronal cells, ultimately leading to hippocampal cognitive attenuation.

show abstract

Section: Discussionmentioning

confidence: 99%

A Pore Forming Toxin-like Protein Derived from Chinese Red Belly Toad Bombina maxima Triggers the Pyroptosis of Hippomal Neural Cells and Impairs the Cognitive Ability of Mice

Wang

Lee

et al. 2023

Toxins

View full text Add to dashboard Cite

show abstract

“…Thus, it is possible that low SES might be related to neuroinflammation via obesity incidence. Additionally, microglia dysregulation may cause myelin damage 80,81 , which could explain the observed association between obesity and RSI-RND. Second, because RSI-RNI increases with normative child development 36 , our findings of greater RSI-RNI, which were corrected for age, may represent accelerated white matter maturation with socioeconomic disadvantage.…”

Section: Discussionmentioning

confidence: 99%

Associations between socioeconomic status and white matter microstructure in children: indirect effects via obesity and cognition

Cai

Taylor

et al. 2023

Preprint

View full text Add to dashboard Cite

Importance Both neighborhood and household socioeconomic disadvantage relate to negative health outcomes and altered brain structure in children. It is unclear whether such findings extend to white matter development, and via what mechanisms socioeconomic status (SES) influences the brain. Objective To test independent associations between neighborhood and household SES indicators and white matter microstructure in children, and examine whether body mass index and cognitive function (a proxy of environmental cognitive/sensory stimulation) may plausibly mediate these associations. Design This cross-sectional study used baseline data from the Adolescent Brain Cognitive Development (ABCD) Study, an ongoing 10-year cohort study tracking child health. Setting School-based recruitment at 21 U.S. sites. Participants Children aged 9 to 11 years and their parents/caregivers completed baseline assessments between October 1st, 2016 and October 31st, 2018. Data analysis was conducted from July to December 2022. Exposures Neighborhood disadvantage was derived from area deprivation indices at primary residence. Household SES indicators were total income and the highest parental education attainment. Main Outcomes and Measures Thirty-one major white matter tracts were segmented from diffusion-weighted images. The Restriction Spectrum Imaging (RSI) model was implemented to measure restricted normalized directional (RND; reflecting oriented myelin organization) and isotropic (RNI; reflecting glial/neuronal cell bodies) diffusion in each tract. Obesity-related measures were body mass index (BMI), BMI z-scores, and waist circumference, and cognitive performance was assessed using the NIH Toolbox Cognition Battery. Linear mixed-effects models tested the associations between SES indicators and scanner-harmonized RSI metrics. Structural equation models examined indirect effects of obesity and cognitive performance in the significant associations between SES and white mater microstructure summary principal components. Analyses were adjusted for age, sex, pubertal development stage, intracranial volume, and head motion. Results The analytical sample included 8842 children (4299 [48.6%] girls; mean age [SD], 9.9 [0.7] years). Greater neighborhood disadvantage and lower parental education were independently associated with lower RSI-RND in forceps major and corticospinal/pyramidal tracts, and had overlapping associations in the superior longitudinal fasciculus. Lower cognition scores and greater obesity-related measures partially accounted for these SES associations with RSI-RND. Lower household income was related to higher RSI-RNI in almost every tract, and greater neighborhood disadvantage had similar effects in primarily frontolimbic tracts. Lower parental education was uniquely linked to higher RSI-RNI in forceps major. Greater obesity-related measures partially accounted for these SES associations with RSI-RNI. Findings were robust in sensitivity analyses and mostly corroborated using traditional diffusion tensor imaging (DTI). Conclusions and Relevance These cross-sectional results demonstrate that both neighborhood and household contexts are relevant to white matter development in children, and suggest cognitive performance and obesity as possible pathways of influence. Interventions targeting obesity reduction and improving cognition from multiple socioeconomic angles may ameliorate brain health in low-SES children.

show abstract

“…Impairment of normal microglial function causes serious effects on normal brain development. MG also regulates myelin growth and integrity in the CNS [ 165 ]. MG interacts with neurons and modulates neuronal activity [ 166 ].…”

Section: Conventional and Novel Targets For Slowing And/or Preventing...mentioning

confidence: 99%

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

Penke

Szücs

Bogár³

2023

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60–80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: β-amyloid (Aβ) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aβ and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aβ and pTau aggregates has been an old drug target. Recently, successful Aβ clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research.

show abstract

Microglia regulate central nervous system myelin growth and integrity

Cited by 191 publications

References 52 publications

A Pore Forming Toxin-like Protein Derived from Chinese Red Belly Toad Bombina maxima Triggers the Pyroptosis of Hippomal Neural Cells and Impairs the Cognitive Ability of Mice

A Pore Forming Toxin-like Protein Derived from Chinese Red Belly Toad Bombina maxima Triggers the Pyroptosis of Hippomal Neural Cells and Impairs the Cognitive Ability of Mice

Associations between socioeconomic status and white matter microstructure in children: indirect effects via obesity and cognition

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

Contact Info

Product

Resources

About